PROJECT SUMMARY Inorganic arsenic (iAs) is a common drinking water and food contaminant poisoning hundreds of millions of individuals around the world, including the US. It has been established that chronic exposure to iAs is associated with risk of type 2 diabetes (T2D) and that metabolism of iAs into its methylated forms is a critical component in determining T2D risk in humans. The methylation of iAs is catalyzed by arsenic methyltransferase (AS3MT). While studies using genome-wide approaches have identified polymorphisms in AS3MT as the major genetic factor determining the inter-individual differences in iAs metabolism, the genetic underpinning of the susceptibility to iAs-associated T2D has never been systematically examined, leaving a critical knowledge gap. Results of population studies carried out by our team suggest that polymorphisms in AS3MT and in several other genes involved in iAs metabolism or in the regulation of glucose homeostasis may also contribute to T2D risk. This project will use the Diversity Outbred (DO) and Collaborative Cross (CC) mouse populations to address this knowledge gap. The central hypothesis of this proposal is that multiple genes and haplotypes (in addition to As3mt) will be tied to diabetic phenotypes associated with iAs exposure. We will first examine the range of metabolic phenotypes in a large cohort of DO mice exposed to iAs. Differences in iAs metabolism will be assessed in both urine and liver. Mice will be genotyped and genetic mapping will lead to identification of Quantitative Trait Loci (QTLs) and founder haplotypes associated with risk and protective alleles. The roles of sex, iAs exposure dose and gene expression as a mediator of haplotype- phenotype relationships will then be established using CC strains with contrasting alleles at the QTLs. Finally, we will assess the roles of the risk loci identified in the mouse cohorts in the inter-individual differences in iAs metabolism and metabolic phenotypes in an existing human cohort in which iAs exposure was linked to T2D The proposed project will be the first to systematically examine genetic foundation of the susceptibility to T2D associated with iAs exposure. Data generated by this project could suggest new risk assessment and prevention strategies in populations where iAs exposures are common and where remediation efforts aiming to reduce human exposure to iAs failed